Abuse and dependence potential of
Cannabis sativa and nabiximols
Professor Jason White Professor of Pharmacology and Head,
School of Pharmacy and Medical Sciences,
Division of Health Sciences,
University of South Australia, Australia
This document has been prepared for the 38th Expert Committee on Drug Dependence 2016.
The author alone is responsible for the views expressed in this publication and they do not
necessarily represent the decisions or policies of the World Health Organization.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 2 of 29
Contents
ACKNOWLEDGEMENTS .................................................................................................... 3
SUMMARY .............................................................................................................................. 3
1 INTRODUCTION.............................................................................................................. 4
1.1 Cannabis sativa ........................................................................................................ 4
1.2 Coverage of the present review ............................................................................... 4
2 CANNABIS AND THC ..................................................................................................... 5
2.1 Animal models of abuse and dependence .............................................................. 5
2.1.1 Mesolimbic dopamine ............................................................................................ 5
2.1.2 Drug discrimination studies ................................................................................... 6
2.1.3 Intracranial self stimulation .................................................................................. 6
2.1.4 Self-administration in animals ............................................................................... 7
2.1.5 Conditioned place preference ................................................................................ 9
2.2 Withdrawal in animals .......................................................................................... 10
2.3 Conclusions from studies using animal models ................................................... 11
2.4 Human studies of abuse potential ......................................................................... 12
2.4.1 Subjective and discriminative effects ................................................................... 12
2.4.2 Choice and self-administration in humans .......................................................... 13
2.5 Withdrawal in humans .......................................................................................... 14
2.6 Epidemiology .......................................................................................................... 15
2.7 Conclusions ............................................................................................................. 16
3 NABIXIMOLS ................................................................................................................. 17
3.1 Animal models of abuse and dependence ............................................................ 17
3.1.1 Intracranial self-stimulation ................................................................................ 17
3.1.2 Conditioned place preference .............................................................................. 17
3.1.3 Drug discrimination studies ................................................................................. 18
3.2 Human abuse potential .......................................................................................... 18
3.3 Withdrawal in humans .......................................................................................... 19
3.4 Conclusions ............................................................................................................. 20
REFERENCES ....................................................................................................................... 21
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 3 of 29
ACKNOWLEDGEMENTS
The author would like to thank Ms Verity Pearson-Dennett, PhD Candidate, Adelaide, South
Australia for her contribution (literature search and review) in producing this report.
SUMMARY
A number of studies in animals and humans, using a variety of methodologies, have assessed
the abuse and dependence potential of cannabis, its main active component THC and
nabiximols (Sativex), the THC/cannabidiol mixture derived from the cannabis plant. The
evidence from animal studies (that have mainly used THC) indicates that it should be
considered a drug of dependence, but that it does not seem as strong a reinforcer as some
other drugs, such as cocaine and morphine: the increase in dopamine in the nucleus
accumbens is not as great and it is not as reliable at lowering self-stimulation threshold,
inducing and maintaining self-administration and inducing conditioned place preference.
Furthermore, the degree of physical dependence is not as pronounced.
Human studies demonstrate that cannabis has significant potential for abuse and dependence:
it has recognisable subjective effects that are mostly considered positive and it is self-
administered. In interpreting these data it should be noted that human experimental studies
may not reflect the range of responses to cannabis in the community as the participants are
almost always cannabis users. Epidemiological evidence supports the potential for abuse of
and dependence on cannabis, but the rates of dependence appear to be lower than for some
other drugs. Cannabis can induce physical dependence among those using the drug frequently,
but the withdrawal syndrome is not considered to be severe.
When THC and cannabidiol are combined as nabiximols, there is little evidence of abuse or
dependence and it seems that there is relatively little potential for either to develop. However,
trials to date have used mainly therapeutic doses and it is possible that supratherapeutic doses
may have some potential for abuse and/or dependence.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 4 of 29
1 INTRODUCTION
1.1 Cannabis sativa
The cannabis plant contains a number of different psychoactive cannabinoids. The primary
psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), was first identified in
the 1960s. THC is a partial agonist of both cannabinoid-type receptors: CB1 and CB2. CB1
receptors are expressed at the highest concentrations in the basal ganglia, cerebellum,
hippocampus, and cerebral cortex, while CB2 receptors are expressed primarily in the
immune system. It is thought that the psychoactive properties of THC arise from its agonist
activity at the CB1 subtype.
1.2 Coverage of the present review
Cannabis, its extracts and tinctures are scheduled (as Schedule I) under the 1961 Convention.
The present review covers cannabis and extracts of cannabis. Currently, there are no
commercially available tinctures of cannabis. One approved medicinal product, nabiximols
(brand name Sativex Oromucosal Spray), is an extract of cannabis. The product is an
oromucosal spray that combines two cannabinoids, THC and cannabidiol, in an approximate
50:50 mixture. Both cannabinoids are present in pure form, but are obtained by a process of
extraction from cannabis leaf and flower. Other constituents of cannabis may also be present
in very small concentrations. In contrast to nabiximols, other products have used synthesized
THC and therefore are not covered under the wording in the 1961 Convention and will not be
included in this review.
This review focuses only on the abuse and dependence potential of cannabis and cannabis
extract in the form of nabiximols. A second review (Amato et al. 2016) considers the medical
uses of cannabis and cannabis extracts and a previous review (Madras 2015) included
considerable detail on the adverse effects of cannabis. The first part of the review considers
the evidence concerning cannabis and THC, from experimental studies on animals and
humans and from epidemiological evidence. Animal studies almost all focus on THC,
whereas human studies are concerned mainly with smoked cannabis. The second section
focuses on nabiximols.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 5 of 29
2 CANNABIS AND THC
2.1 Animal models of abuse and dependence
There are a number of animal models that have been used to assess the abuse and dependence
potential of CNS active drugs. While each has its limitations, in general they have a high
degree of predictive ability, particularly when used in combination. The advantage of animal
models is the ability to separate inherent biological actions of the drug that predispose to the
development of abuse and dependence from individual (including genetic) characteristics and
social and other environmental factors that influence human drug use.
2.1.1 Mesolimbic dopamine
Activation of the mesolimbic dopamine system has been implicated as the key neural event
that underlies drug reinforcement and the development of drug dependence. The mesolimibic
dopamine system comprises a group of neurons with cell bodies in the ventral tegmental area
(VTA) and axonal terminals in the nucleus accumbens (NAcc). Drugs that are commonly
abused, such as opioids, ethanol, nicotine, amphetamine and cocaine increase extracellular
dopamine concentrations in the NAcc, but especially in the shell of the NAcc (Di Chiara &
Imperato 1988). In contrast, drugs without such action are not generally subject to abuse and
dependence. The increase in dopamine can be due to activation of dopamine neurons in the
VTA (e.g. nicotine), decreased inhibition of VTA neurons (e.g. opioids) or through direct
synaptic action in the NAcc (e.g. cocaine, amphetamine).
Administration of THC to rats has been shown to result in a dose-dependent increase in the
firing rate of VTA dopaminergic neurons (French, Dillon & Wu 1997), and increased levels
of extracellular dopamine in the shell of the NAcc (Tanda, Pontieri & Di Chiara 1997). At the
doses tested, this increase in dopamine was significant, but of lesser magnitude than the
increase produced by heroin. The THC-induced increase was blocked by the CB1 antagonist
rimonabant and at least partially blocked by the opioid receptor antagonist naloxone,
suggesting an opioid influence on the mechanism of action. The increase in dopamine has
also been shown to be associated with self-administered THC (Fadda et al. 2006).
While widespread in the brain, including the VTA and the NAcc, CB1 receptors are not
found on dopaminergic neurons. However, there is evidence from a variety of studies
suggesting that the increase in dopamine in the NAcc is due to reduction in the inhibitory
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 6 of 29
actions of GABAergic neurons, a mechanism similar to opioids (Pierce & Kumaresan 2006;
Oleson & Cheer 2012).
2.1.2 Drug discrimination studies
Drug discrimination studies in animals are considered as a model for subjective drug effects
in humans (Swedberg & Giarola 2015). In drug discrimination studies, animals are typically
trained to respond in one manner when administered a drug and in a second manner when
they have been administered vehicle or placebo. Correct responses are reinforced with food
or some other reward. The discrimination between drug and placebo is assumed to be based
upon the presence or absence of perceivable central nervous system effects of the drug. The
characteristics of these effects can then be determined by administration of other substances
either alone or in conjunction with the drug used for training. In general, drugs that have
subjective effects in humans can be discriminated by animals, whereas those that do not have
such effects cannot be discriminated, and drugs with similar subjective effects in humans are
discriminated as similar by animals.
There are a number of studies of drug discrimination using THC in animals, using a variety
of species, including rats, mice and rhesus monkeys. They show that animals can learn to
reliably discriminate THC and that the THC discriminative stimulus shows a high degree of
specificity (for example see Balster & Prescott 1992). While drugs from other
pharmacological classes failed to substitute for THC, a number of synthetic and natural
cannabinoids (e.g. levonantradol, nabilone, Δ8-tetrahydrocannabinol) have been found to
have THC-like discriminative stimulus effects (Barrett et al. 1995). The discriminative
stimulus effects of THC can be blocked by the CB1 receptor antagonist rimonabant (Wiley et
al. 1995; Vann et al. 2009), indicating that the THC discriminative stimulus is CB1 mediated.
2.1.3 Intracranial self stimulation
Intracranial self-stimulation (ICSS) refers to the reinforcing effects of currents administered
to certain parts of the brain (so-called ‘reward centres’). The threshold current required to
produce such reinforcement is a measure of reward activity and can be used to assess and
compare the abuse liability of drugs. Lowering of the ICSS threshold indicates a facilitation
of brain stimulation reward, whereas elevation of the threshold reflects diminished reward
value of the stimulation. Acute administration of most drugs of abuse (e.g. cocaine,
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 7 of 29
amphetamine, morphine) lowers the ICSS threshold, reflecting an increase in activity in the
neural substrates of reward due to the action of the drug. In contrast, withdrawal from chronic
administration of these compounds results in an elevation of ICSS threshold, reflecting the
decrease in reward activity compared to the normal state. These actions are presumed to
model the respective positive and negative affective states of drug intoxication and drug
withdrawal in humans.
Using this model, the results to date with THC have been contradictory. In some studies,
THC has been shown to lower the threshold for electrical stimulation. For example,
significant reductions in self stimulation threshold were recorded in Lewis rats 15 and 30
minutes after administration of 1.5 mg/kg THC (Gardner et al. 1988). In contrast, a
significant increase in the self-stimulation threshold was observed in Sprague Dawley rats
administered 1 and 2 mg/kg THC intraperitoneally (Vlachou et al. 2007). The differences
may be attributable to variations in results between strains, with Lewis rats showing
decreases in threshold that have not been seen with other strains (Lepore et al. 1996; Vlachou
& Panagis 2014). However, other aspects of the methodology used, such as dose, could also
have played a role.
It appears that THC is not as effective at reliably reducing ICSS threshold compared to some
other drugs of abuse. This could be indicative of lower abuse potential, although it also needs
to be recognized that the number of studies in this area is small and that this methodology is
not as effective at predicting abuse potential as some others.
2.1.4 Self-administration in animals
Drugs that are commonly abused by humans are also typically self-administered by
laboratory animals under controlled experimental conditions. Self-administration in animal
models is considered to be one of the most reliable predictors of abuse potential in humans.
Self-administration studies allow animals to self-administer a drug by performing an operant
response, such as pressing a lever. Measures recorded include the number of lever presses per
minute (rate of responding), the number of self-administered doses and the frequency of
doses delivered in the session, and the total drug intake during the session. The studies are
often performed in animals that have previously learnt to self-administer a training drug (a
recognized drug of abuse such as cocaine) and require a fixed number of responses to obtain
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 8 of 29
an injection of the drug (‘reward’). The drug to be tested is then substituted for the training
drug and assessed for its ability to produce equivalent or greater levels of responding than
those maintained during training.
It is well established that laboratory animals will self-administer most drugs that are abused
by humans. For example, cocaine is self-administered under a wide range of experimental
conditions and in a number of different species (Kelleher & Goldberg 1977; Griffiths,
Bradford & Brady 1979; Bergman et al. 1989). Animals will also reliably self-administer a
range of opioids, including morphine, heroin, and codeine (Jones, BE & Prada 1977; Mello
1991). In contrast, early laboratory animal studies failed to clearly demonstrate persistent,
dose-related, self-administration behaviour maintained by THC (for review see Justinova et
al. 2005). There were some examples of self-administration, but these occurred under limited
experimental conditions. For example, Takahashi and Singer (1979) demonstrated THC self-
administration in drug naïve, diet restricted rats exposed to a schedule of intermittent food
delivery that has been shown to produce a variety of ‘excessive’ behaviours. These animals,
which were maintained at 80% body weight, self-administered low dose THC, but self-
administration immediately returned to placebo levels when food restriction was discontinued.
THC self-administration has been established in squirrel monkeys in one laboratory (Tanda,
Munzar & Goldberg 2000; Justinova et al. 2004; Justinova et al. 2003). Tanda, Munzar and
Goldberg (2000) demonstrated persistent THC self-administration using doses of THC
similar to those inhaled by human cannabis users. Squirrel monkeys were initially trained to
press a lever for an i.v. injection of cocaine, with 10 lever presses resulting in a 30 μg/kg
injection (fixed-ratio 10; FR10). A five-session washout period, where saline was substituted
for cocaine, was implemented prior to testing THC. Responding increased following
substitution of 2 μg/kg injections of THC for saline and stabilized within a week.
Approximately 30 injections of THC were self-administered per session, a rate comparable to
that maintained by cocaine under identical conditions (Tanda, Munzar & Goldberg 2000).
While early studies relied on first training animals to self-administer cocaine, THC self-
administration has also been shown in drug-naïve squirrel monkeys using the same dosing
schedule. THC was found to maintain significantly higher numbers of doses
self-administered per session and higher rates of responding than vehicle at doses of 2, 4 and
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 9 of 29
8 μg/kg per injection (Justinova et al. 2003). The response rates maintained by the drug-naïve
squirrel monkeys under the fixed-ratio were similar to or greater than peak responding rates
maintained by i.v. cocaine (Spear et al. 1991), nicotine (Sannerud et al. 1994) and midazolam
(Munzar et al. 2001). Pre-treatment with naltrexone was shown to reduce THC self-
administration, but not to the level of placebo, suggesting a role of the opioid system in the
rewarding effects of cannabis (Justinova et al. 2004).
It appears that self-administration of THC may be somewhat species-specific. Confirming
earlier studies, a very recent report indicates that under optimal training conditions, THC is
only a weak reinforcer in rats (Wakeford et al. 2016). In contrast, under the same conditions,
cocaine produced reliable self-administration. While primates are a somewhat closer model
to humans than rats, the lack of species generality may suggest that the reinforcing properties
of THC are not as robust as some other drugs of abuse.
2.1.5 Conditioned place preference
The conditioned place preference (CPP) test is considered to measure the rewarding effects of
a drug in a manner that is less affected by the direct behavioural effects of the drug
(stimulation or sedation) than self-administration. CPP involves periods of exposure to a
compartment on one side of an apparatus under the influence of the drug and exposure to the
compartment on the other side after placebo. The two compartments are made physically
distinctive. The animals are then given a choice between the sides and preference (CPP) is
demonstrated if the animals are found to spend significantly more time in the drug-paired
compartment compared to the non-drug (placebo or vehicle) compartment (Bardo, Horton &
Yates 2015). Conditioned place aversion (CPA) is found if the animal spends significantly
more time in the non-drug compartment than the drug compartment.
There are a number of studies of CPP/CPA in rats and mice using THC and the results have
been somewhat inconsistent (for a summary see Vlachou & Panagis 2014). In many instances,
THC induces CPA rather than CPP in rats and mice, particularly at high doses (e.g. 15-20
mg/kg) (Sañudo-Peña et al. 1997; Hutcheson et al. 1998; Schramm-Sapyta et al. 2007).
Lepore et al. (1995) compared the rewarding properties of THC with cocaine and morphine
in Long-Evans rats. Administration of 1 mg/kg THC resulted in neither CPA nor CPP,
however higher doses of THC (2 and 4 mg/kg) produced a preference for the THC
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 10 of 29
compartment. The CPP observed at these doses was less than that produced by low dose
cocaine and morphine. In the same study, changes in the timing of drug exposure resulted in
CPA at the higher THC doses. CPP has been observed in Sprague-Dawley and Wistar rats at
THC doses ranging from 0.075-0.75 mg/kg (Braida et al. 2004; Le Foll, Wiggins & Goldberg
2006).
Schramm-Sapyta et al. (2007) showed only CPA, which was stronger in adult compared to
adolescent rats. In addition, they found that THC was anxiogenic in two rodent models of
anxiety, the elevated plus maze and the light-dark test. In both models, the anxiogenic effects
were stronger in adult compared to adolescent rats. They suggested that these anxiogenic
effects may underlie the CPA they observed.
The evidence using the CPP/CPA procedure suggests that, like the results from the self-
administration procedure, THC can have reinforcing effects, but they may not be as robust or
strong as for some other drugs of abuse. There is also evidence of the ability of THC to
produce aversion rather than rewarding effects.
2.2 Withdrawal in animals
Withdrawal studies involve chronic administration of the drug to animals followed by abrupt
cessation or administration of an antagonist. The disruptive effects of withdrawal can be
determined by measurement of changes in the animals’ behavior, while the negative reward
value can be measured using CPA and changes in ICSS threshold. Changes to dopaminergic
activity in the NAcc can also be measured in withdrawal states.
A range of behavioural changes associated with THC withdrawal have been observed in
laboratory animals. Aggressive behaviour, hyperirritability, tremors, photophobia, anorexia,
and apparent hallucinations have been reported in rhesus monkeys following cessation of
long-term THC administration (Kaymakcalan 1972). A study by Aceto et al. (1996) found the
most common withdrawal signs in rats were scratching, licking, arched back, and ptosis.
Following cessation of high dose continuous infusions (12.5-50 mg/kg/24 hrs for 4 days), rats
also displayed biting, tongue rolling, retropulsion, and ataxia. Administration of the CB1
antagonist rimonabant (SR141716A) following twice-daily THC administration in mice
resulted in an increase in paw tremors and headshakes and a decrease in normal behaviour
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 11 of 29
such as grooming and scratching (Cook, Lowe & Martin 1998). Disruption of operant
behavior during cessation of chronic THC administration indicative of dependence or by
rimonabant-precipitated withdrawal has also been reported in rhesus monkeys (Beardsley et
al., 1986) and in rats (Beardsley and Martin, 2000), respectively .
Using ICSS threshold, withdrawal from THC has been demonstrated in rats following a
single 1 mg/kg dose of THC. Brain reward threshold was significantly increased in the period
after cessation of THC effects, with the change lasting approximately 24 hours (Gardner &
Vorel 1998). In rats repeatedly administered THC, dopaminergic neuronal activity in the
VTA and dopamine release in the NAcc are reduced following abrupt THC discontinuation
or administration of a selective CB1 antagonist (Diana et al. 1998; Tanda, Loddo & Di Chiara
1999). These changes in the mesolimbic pathway have also been observed in the early phase
of withdrawal following chronic exposure to amphetamine, cocaine, and morphine (Rossetti,
Hmaidan & Gessa 1992).
2.3 Conclusions from studies using animal models
In animal models, THC shows a number of the characteristics of a drug of dependence. In
particular, it:
has discriminative effects that are linked to its receptor action (although it is
important to recognize that drugs that are not abused also have discriminative effects),
increases dopamine concentration in the shell of the NAcc
lowers ICSS threshold
is self-administered, and
induces CPP (at least under some experimental conditions)
In addition, cessation of administration of THC is associated with a withdrawal syndrome
that is both behaviourally disruptive and aversive in nature.
It is reasonable to conclude from these studies that THC should be considered a drug of
dependence in the same way as a range of opioids, stimulants, etc. Nevertheless, there is
some evidence that it is not as strong a reinforcer as some other drugs, such as cocaine,
heroin and morphine: the increase in NAcc dopamine is not as great as that occurring with
some other drugs and it is not as reliable at lowering ICSS threshold, inducing and
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 12 of 29
maintaining self-administration and inducing CPP as at least some other drugs of dependence.
It should be recognised, however, that the evidential basis for direct comparison of THC with
other drugs is limited and therefore the conclusion is a cautious one.
2.4 Human studies of abuse potential
There are a range of methods that have been used to experimentally assess the abuse potential
of drugs in humans. Some of these parallel the methods used in animals (e.g. self-
administration), while others, such as the self-reporting of subjective effects, are different.
Some techniques used in animals cannot be used in humans (e.g. ICSS thresholds). In
addition, for ethical reasons, participants in human studies are normally limited only to those
people who have prior experience of cannabis use; in many instances they are frequent
cannabis users. This means that they are a self-selected population who may not reflect the
range of responses to cannabis across the population.
2.4.1 Subjective and discriminative effects
Cannabis produces clear subjective reports of pleasurable effects and these are associated
with motivational responses, including drug-seeking and drug-taking behaviour. Euphoria or
a feeling of ‘high’ has been identified as a primary factor associated with cannabis use,
however changes in perception, feelings of relaxation, appetite and occasionally dysphoria
are also reported (Kleinloog et al. 2014; Green, Kavanagh & Young 2003). The dysphoric
effects are mainly related to anxiety. From limited data, it appears that the strength of
subjective effects is correlated, to at least some extent, with blood THC concentration
(Hartman et al. 2015).
It is important to note that comparing the subjective effects of THC between studies can be
difficult due to differences in smoking protocols between studies (i.e. varying cigarette THC
content, paced smoking protocol where number of puffs, duration of puffs and smoking
interval are controlled) as well as variation in smoking between participants within studies.
However, research to date has shown no significant differences in smoking measures (i.e.
number of puffs, duration of puffs, and smoking interval) between cigarettes containing
different concentrations of THC (0.2, 0.4, and 0.8% THC, Cappell, Kuchar & Webster 1973;
1.32, 1.97, and 2.54% THC, Perez-Reyes et al. 1982).
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 13 of 29
The subjective effects produced by oral THC have been reported to be of a similar intensity
to those described following smoked cannabis. For example, a study by Hart and colleagues
(2002) reported that smoked cannabis (3.1% THC) and oral THC (20 mg) produced
comparable increases in ratings of ‘good effects’, ‘high’, and ‘liking’ on a 50-item subjective-
effects visual analog questionnaire. Adolescents with cannabis use disorders report increased
ratings of ‘good drug effect’, ‘high’, and ‘drug liking’ following 10 mg oral THC (Gray et al.
2008).
A study by Chait and colleagues (1988) demonstrated that experienced cannabis users could
reliably learn to discriminate cannabis from placebo cigarettes. Participants could correctly
identify the training dose (2.7% THC cigarettes) within 90 seconds of commencing smoking.
The effect was dose dependent, with lower THC cigarettes producing proportionally lower
drug appropriate responses.
Lile et al. (2009) established a 25mg oral dose of THC as a discriminative stimulus in
moderate cannabis users. The participants learned to identify the stimulus reliably and
showed graded responses to lower doses of the drug. There was no overlap with other
psychoactive drugs tested, but, in a subsequent study, the synthetic cannabinoid nabilone was
shown to produce THC-like discriminative effects (Lile, Kelly & Hays 2010).
2.4.2 Choice and self-administration in humans
In humans, cigarettes with a higher concentration of THC are preferred over cigarettes with
lower THC concentrations (Mendelson & Mello 1984; Kelly et al. 1997). For example, Chait
and Burke (1994) allowed subjects to sample low-potency cannabis (0.63% THC) cigarettes
and high potency cannabis (1.95% THC) cigarettes prior to a choice session. Subjects chose
high-potency cannabis cigarettes on 21 of 24 occasions. In addition, when participants chose
between a cannabis cigarette and an alternative reward such as food or money, cannabis was
chosen over the alternative reward more often when the THC content was higher (e.g. Haney
et al. 1997). These results suggest that the reinforcing strength of cannabis is related to THC
content. However, the choice to self-administer THC can often be reduced when an
alternative reinforcer (e.g. money) is concurrently available (Haney et al. 1997; Hart et al.
2002).
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 14 of 29
Human subjects will also choose oral THC over placebo. Chait and Zacny (1992)
investigated the reinforcing and subjective effects of smoked cannabis and oral THC. All
subjects chose smoked cannabis over placebo, and 10 out of 11 subjects chose oral THC over
placebo.
2.5 Withdrawal in humans
The cannabis withdrawal syndrome has been well characterised. It has some elements in
common with withdrawal from other drugs, but the overall withdrawal symptom profile is
unique to cannabis (Vandrey et al. 2008; Vandrey et al. 2005). Following cessation of heavy
cannabis use, patients experience craving, irritability, anger, depression, difficulty sleeping,
and decreased appetite (Budney et al. 2008). Most symptoms begin within 24 to 48 hours of
abstinence and peak within 4 to 6 days (Haney et al. 1999). Withdrawal symptoms can last
from 1 to 3 weeks, although significant individual differences occur. Unlike opioid,
amphetamine or alcohol withdrawal syndromes, cannabis withdrawal does not appear to
include severe or life-threatening medical consequences or major psychiatric disturbances
and is therefore considered mild (Carlson et al. 2012; McKeon, Frye & Delanty 2008; Ashton
2005).
The most common withdrawal symptoms observed in 49 dependent cannabis users during
two weeks of abstinence were sleep disturbances (nightmares or strange dreams, 41%;
trouble getting to sleep, 37%; waking up early, 33%; waking up sweating, 32%), mood
changes (angry outburst, 27%; irritated, 30%; feeling tense, 27%) and gastrointestinal
symptoms (loss of appetite, 27%; nausea, 19%; stomach ache, 19%) (Allsop et al. 2011). Lee
et al. (2014) characterised the prevalence, duration, and intensity of withdrawal and craving
effects in 30 male chronic, frequent cannabis smokers during abstinence on a closed research
unit. The most frequently reported symptoms based on self-report using visual analogue
scales (VAS) were craving cannabis (48%), irritability (37%), angry/aggressive (36%),
depressed (31%), feeling anxious (29%), and restless (27%). Peak abstinence symptoms were
observed on days 0-3, with most symptoms declining thereafter. In contrast, difficulty getting
to sleep and strange dreams were found to increase over time, suggesting that chronic
cannabis users may have intrinsic sleep problems that may have predisposed them to use
cannabis.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 15 of 29
The effectiveness of oral THC in suppressing cannabis withdrawal has been tested in
cannabis users (Budney et al. 2007). Administration of doses of 10-30mg THC suppressed
symptoms including craving, irritability, aggression and overall discomfort in a dose
dependent manner. At the higher doses, symptoms were only a little above the level reported
by participants prior to withdrawal. While other components of cannabis smoke may play
some role in physical dependence, these findings highlight the central role of THC.
It has also been demonstrated that THC alone is able to induce physical dependence.
Withdrawal symptoms have been reported following interruption of oral THC dosing:
irritability, restlessness, sleep disturbances, and decreased appetite were observed in subjects
following abrupt cessation of high dose oral THC (210 mg/kg for 10-20 days) (Jones, RT,
Benowitz & Bachman 1976). Subsequent administration of THC was able to diminish the
withdrawal symptoms.
2.6 Epidemiology
It is estimated that in 2014, 3.8% of the global population had recently (past 12 months) used
cannabis (UNODC 2016). While estimates of cannabis use are generally well reported, the
extent of cannabis abuse and dependence is not known. Degenhardt et al. (2011) conducted a
systematic analysis of available data on the extent of global illicit drug use and dependence.
The results show that only seven countries had reported estimates of cannabis dependence:
four national estimates and three subnational estimates. Estimates of cannabis dependence
ranged from 0.4% (Germany; estimate year 2006) to 9.4% (New Zealand; estimate year
2000).
Another epidemiological study estimated the population level of cannabis dependence across
Western and Eastern Europe, America, Australia and Southeast Asia with figures ranging
from 0.1-1.5% (Degenhardt & Hall 2012). A more recent epidemiological study estimated
that there were 13.1 million cannabis dependent people globally in 2010 (Degenhardt et al.
2013). Prevalence of cannabis dependence was greater in people aged 20-24 years, and was
higher in males than females.
Figures from the US show an increasing rate of cannabis use in the population between 2001-
2 and 2012-3 (Hasin et al. 2015). The number of users with a cannabis disorder (defined as
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 16 of 29
cannabis abuse or dependence according to DSM-IV criteria) also increased, but the
proportion did not significantly change. These authors estimated that in the US in 2012-3,
approximately 27% of cannabis users had a cannabis disorder. This is higher than the figures
above, but this also included cannabis abuse and therefore those who were not dependent but
had experienced adverse effects from their cannabis use.
In order to assess the dependence potential of cannabis, estimates need to be made of
dependence among users. Ideally, these would then be compared to the risk of dependence
among users of other drugs. The only estimates of this nature have been made from US data
in the 1990s (Anthony, Warner & Kessler 1994) and then approximately 10 years later
(Wagner & Anthony 2002). The first estimates show that the rates of dependence among non-
medical drug users were as follows: tobacco 32%, heroin 23%, cocaine 17%, alcohol 15%,
cannabis 9%, anxiolytics and sedatives 9%. The subsequent estimates show a rate of
dependence of 8% for cannabis compared to 12-13% for alcohol and 15-16% for cocaine. It
should be recognised that these figures are particular to one country and a limited time period,
and are likely to vary according to factors such as drug availability and prevailing social
sanctions. Nevertheless, they show that while there is a significant rate of dependence among
people who have used cannabis, it is somewhat lower than the rates for a number of other
drugs.
2.7 Conclusions
The results from studies in humans indicate that cannabis has significant potential for abuse
and dependence: it has recognisable subjective effects, it produces effects that are mostly
considered positive and it is self-administered. As noted earlier, these results largely come
from a self-selected population of cannabis users and it is possible that in a random group
from the population the responses would be more diverse and include some people for whom
cannabis was not reinforcing. Epidemiological evidence supports the potential for abuse of
and dependence on cannabis. However, the rates of dependence may be lower than for some
other drugs.
Cannabis can induce physical dependence, but the withdrawal syndrome is not considered to
be severe and is certainly less pronounced than withdrawal from opioids and alcohol.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 17 of 29
The evidence to date suggests that the abuse and dependence potential of cannabis are largely
due to the actions of THC, although a role for other cannabinoids cannot be excluded.
3 NABIXIMOLS
While the abuse potential of cannabis has been widely studied, less is known regarding the
abuse potential of nabiximols. Nabiximols is an approximate 1:1 ratio of THC and
cannabidiol (CBD) with small concentrations of other cannabis constituents delivered as an
oromucosal spray. It therefore differs from cannabis in the cannabinoid composition and in
the route of administration. The abuse and dependence potential of THC has been presented
above, therefore this section will consider the current information on the abuse and
dependence potential of nabiximols (THC+CBD). CBD will be considered to the extent that
it informs the likely actions and effects of nabiximols, particularly in studies using animal
models.
Unlike THC, CBD appears to have no agonist activity at either CB1 or CB2 receptors, but
may act as an antagonist at these sites (Petwee 2008). CBD interacts with many other
non-endocannabinoid receptors, including the 5-HT1A receptor and vanilloid receptor type 1
(Bisogno et al. 2001; Zuardi 2008). CBD may additionally affect cannabinoid systems by
enhancing the action of the endogenous cannabinoid ligand anandamide. This results from
blockade of anandamide reuptake and the inhibition of its enzymatic degradation (Bisogno et
al. 2001; Mechoulam & Hanuš 2002).
3.1 Animal models of abuse and dependence
3.1.1 Intracranial self-stimulation
In male Sprague-Dawley rats, administration of low dose (5 mg/kg) CBD did not change the
threshold frequency required for ICSS, however high dose (10 mg/kg and 20 mg/kg) CBD
resulted in an elevation of the threshold (Katsidoni, Anagnostou & Panagis 2013).
3.1.2 Conditioned place preference
It appears that CBD given alone has little effect on place conditioning. For example, Long-
Evans rats treated with 10 mg/kg CBD showed neither CPP nor CPA (Vann et al. 2008).
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 18 of 29
However, rats treated with increasing doses of CBD and THC (1, 3, and 10 mg/kg) exhibited
a trend towards CPP not seen in those given THC alone (Klein et al. 2011). The authors
attributed this to a pharmacokinetic interaction leading to higher THC concentrations rather
than a change in receptor action.
3.1.3 Drug discrimination studies
CBD appears not to exhibit THC-like discriminative stimulus effects. For example, CBD did
not produce the level of responses induced by THC in Long-Evans rats (Vann et al. 2008).
CBD also failed to substitute for THC in pigeons trained to discriminate THC from vehicle
(Jarbe, Henriksson & Ohlin 1977). Co-administration of THC and CBD at ratios similar to
those in nabiximols did not result in changes in THC-lever responding, suggesting that CBD
may not significantly alter the subjective effects of THC.
3.2 Human abuse potential
Only one study has had the primary aim of investigating the abuse potential of nabiximols
using a randomized, double blind, crossover design. In the study by Schoedel et al. (2011),
experienced cannabis smokers received, in random order, single administrations of placebo;
nabiximols 4 sprays (equivalent to 10.8 mg THC, 10 mg CBD: low dose), 8 sprays
(equivalent to 21.6 mg THC and 20 mg CBD: medium dose) and 16 sprays (equivalent to
43.2 mg THC and 40 mg CBD: high dose); and dronabinol (synthetic THC) 20 mg (medium
dose) and 40 mg (high dose). Low dose nabiximols was found not to differ significantly from
placebo on measures of ‘drug liking’, euphoria, or subjective drug value, while medium and
high doses showed evidence of abuse potential in comparison with placebo. However, the
effects with nabiximols were consistently lower on a dose-for-dose basis compared to
dronabinol.
To date there have been no reports of misuse of nabiximols. In clinical trials, the incidence of
intoxication and euphoria has been low (Robson 2011). For example, Wade et al. (2006)
investigated the safety and efficacy of long-term term treatment with nabiximols. Patients
entering the study had reported initial benefits from nabiximols treatment following a four-
week open label, placebo control period. Median intoxication scores (measured daily by
VAS) were <5 out of 100 at all time points, and only three (2%) patients withdrew due to
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 19 of 29
symptoms possibly associated with intoxication (confusion, light headedness, somnolence).
Low levels of intoxication were also reported in a six week randomized, double blind study.
Mean intoxication scores remained below 2 (measured on a numerical rating scale; 0, no
intoxication; 10, extreme intoxication), and less than 4% of subjects receiving nabiximols
reported euphoric mood (Collin et al. 2007).
Patients receiving nabiximols at a supratherapeutic dose (36 sprays per day) reported greater
levels of events potentially associated with intoxication; these included somnolence (49%),
euphoric mood (39%), and disorientation (15%) (Sellers et al. 2013). By comparison,
euphoria was reported in 7% of subjects receiving placebo and 17% of subjects receiving
therapeutic doses (8 sprays per day). This suggests that nabiximols has a dose-related
euphoric effect that is relatively low at therapeutic dose levels.
Self-reported intoxication scores have been found to decrease following chronic use,
consistent with the development of tolerance. Serpell, Notcutt and Collin (2013) reported
intoxication scores following acute (initial dosing) and chronic (≥4 weeks) exposure.
Intoxication scores (measured using 100 mm VAS) increased to 12.4±18.9 mm two hours
after the first dose. Intoxication scores then decreased following chronic dosing, and at the
last observed visit the mean was 3.1±8.3 mm. In addition, only 4.8% of patients receiving
nabiximols reported euphoric mood.
3.3 Withdrawal in humans
To date there is limited evidence of a withdrawal syndrome associated with cessation of
nabiximols treatment, and abrupt withdrawal from long-term use has produced only mild and
temporary disturbance of sleep, mood and appetite in a small number of subjects (Robson
2011).
A study by Wade et al. (2006) investigated the effects of a planned, sudden two-week
interruption of long-term nabiximols treatment (mean duration of study participation 434
days; range 21-814). No consistent withdrawal syndrome was observed, however 11 of the 25
(44%) subjects experienced symptoms potentially associated with withdrawal including:
interrupted sleep (16%), hot and cold flushes (16%), tiredness (16%), low mood (12%),
decreased appetite (8%), mood swings (4%), vivid dreams (4%), and intoxication (4%).
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 20 of 29
Notcutt et al. (2012) randomly allocated nabiximols maintained multiple sclerosis patients
(average nabiximols treatment 3.6 years) to continue with nabiximols (n=18) or to change to
placebo (n=18). No withdrawal syndrome was observed, however 2% of the group changing
to placebo reported depressed mood.
3.4 Conclusions
It appears that cannabidiol itself has little or no potential for abuse. It may moderate some of
the effects of THC, but the changes have been small and the direction inconsistent.
When THC and cannabidiol are combined as nabiximols, there is little evidence of abuse or
dependence and relatively little potential for those to develop. However, trials to date have
used mainly therapeutic doses and it is possible that supratherapeutic doses may have some
potential for abuse and/or dependence. At this stage, while the evidence for the effects of
such doses is limited, the extant evidence suggests that abuse potential of nabiximols may be
lower than that of THC.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 21 of 29
REFERENCES
Aceto, MD, Scates, SM, Lowe, JA & Martin, BR 1996, 'Dependence on Δ9-
tetrahydrocannabinol: Studies on precipitated and abrupt withdrawal', Journal of
Pharmacology and Experimental Therapeutics, vol. 278, no. 3, pp. 1290-1295.
Allsop, DJ, Norberg, MM, Copeland, J, Fu, S & Budney, AJ 2011, 'The Cannabis
Withdrawal Scale development: Patterns and predictors of cannabis withdrawal and
distress', Drug and Alcohol Dependence, vol. 119, no. 1-2, pp. 123-129.
Amato, L et al 2016 Systematic reviews on therapeutic efficacy and safety of
Cannabis (including extracts and tinctures) for patients with multiple sclerosis,
chronic neuropathic pain, dementia and Tourette Syndrome, HIV/AIDS, cancer
assuming chemotherapy.
Anthony, JC, Warner, LA & Kessler, RC 1994, 'Comparative epidemiology of
dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings
from the National Comorbidity Survey', Experimental and Clinical
Psychopharmacology, vol. 2, no. 3, pp. 244-268.
Ashton, H 2005, 'The diagnosis and management of benzodiazepine dependence',
Current Opinion in Psychiatry, vol. 18, no. 3, pp. 249-255.
Balster, RL & Prescott, WR 1992, 'Δ9-Tetrahydrocannabinol discrimination in rats as
a model for cannabis intoxication', Neuroscience and Biobehavioral Reviews, vol. 16,
no. 1, pp. 55-62.
Bardo, MT, Horton, DB & Yates, JR 2015, 'Conditioned Place Preference as a
Preclinical Model for Screening Pharmacotherapies for Drug Abuse', Nonclinical
Assessment of Abuse Potential for New Pharmaceuticals, Elsevier Inc., pp. 151-196.
Barrett, RL, Wiley, JL, Balster, RL & Martin, BR 1995, 'Pharmacological specificity
of delta 9-tetrahydrocannabinol discrimination in rats', Psychopharmacology, vol. 118,
no. 4, pp. 419-424.
Beardsley PM, Balster RL, Harris LS 1986, 'Dependence on tetrahydrocannabinol in
rhesus monkeys', Journal of Pharmacology and Experimental Therapeutics,vol 239,
no. 2, pp. 311-9.
Beardsley PM, Martin BR 2000, 'Effects of the cannabinoid CB(1) receptor
antagonist, SR141716A, after Delta(9)-tetrahydrocannabinol withdrawal', European
Journal of Pharmacology, vol. 387, no. 1, pp. 47-53.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 22 of 29
Bergman, J, Madras, BK, Johnson, SE & Spealman, RD 1989, 'Effects of cocaine and
related drugs in nonhuman primates. III. Self-administration by squirrel monkeys',
Journal of Pharmacology and Experimental Therapeutics, vol. 251, no. 1, pp. 150-
155.
Bisogno, T, Hanuš, L, De Petrocellis, L, Tchilibon, S, Ponde, DE, Brandi, I, Moriello,
AS, Davis, JB, Mechoulam, R & Di Marzo, V 2001, 'Molecular targets for
cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the
cellular uptake and enzymatic hydrolysis of anandamide', British Journal of
Pharmacology, vol. 134, no. 4, pp. 845-852.
Braida, D, Iosuè, S, Pegorini, S & Sala, M 2004, 'Δ 9-Tetrahydrocannabinol-induced
conditioned place preference and intracerebroventricular self-administration in rats',
European Journal of Pharmacology, vol. 506, no. 1, pp. 63-69.
Budney, AJ, Vandrey, RG, Hughes, JR, Moore, BA & Bahrenburg, B 2007, 'Oral
delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms', Drug and
Alcohol Dependence, vol. 86, no. 1, pp. 22-29.
Budney, AJ, Vandrey, RG, Hughes, JR, Thostenson, JD & Bursac, Z 2008,
'Comparison of cannabis and tobacco withdrawal: Severity and contribution to relapse',
Journal of Substance Abuse Treatment, vol. 35, no. 4, pp. 362-368.
Cappell, H, Kuchar, E & Webster, CD 1973, 'Some correlates of marihuana self-
administration in man: A study of titration of intake as a function of drug potency',
Psychopharmacologia, vol. 29, no. 3, pp. 177-184.
Carlson, RW, Kumar, NN, Wong-Mckinstry, E, Ayyagari, S, Puri, N, Jackson, FK &
Shashikumar, S 2012, 'Alcohol Withdrawal Syndrome', Critical Care Clinics, vol. 28,
no. 4, pp. 549-585.
Chait, LD, Evans, SM, Grant, KA, Kamien, JB, Johanson, CE & Schuster, CR 1988,
'Discriminative stimulus and subjective effects of smoked marijuana in humans',
Psychopharmacology, vol. 94, no. 2, pp. 206-212.
Chait, LD & Zacny, JP 1992, 'Reinforcing and subjective effects of oral Δ9-THC and
smoked marijuana in humans', Psychopharmacology, vol. 107, no. 2-3, pp. 255-262.
Chait, LD & Burke, KA 1994, 'Preference for high- versus low-potency marijuana',
Pharmacology, Biochemistry and Behavior, vol. 49, no. 3, pp. 643-647.
Collin, C, Davies, P, Mutiboko, IK & Ratcliffe, S 2007, 'Randomized controlled trial
of cannabis-based medicine in spasticity caused by multiple sclerosis', European
Journal of Neurology, vol. 14, no. 3, pp. 290-296.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 23 of 29
Cook, SA, Lowe, JA & Martin, BR 1998, 'CB1 receptor antagonist precipitates
withdrawal in mice exposed to δ9- tetrahydrocannabinol', Journal of Pharmacology
and Experimental Therapeutics, vol. 285, no. 3, pp. 1150-1156.
Degenhardt, L, Bucello, C, Calabria, B, Nelson, P, Roberts, A, Hall, W, Lynskey, M
& Wiessing, L 2011, 'What data are available on the extent of illicit drug use and
dependence globally? Results of four systematic reviews', Drug and Alcohol
Dependence, vol. 117, no. 2-3, pp. 85-101.
Degenhardt, L & Hall, W 2012, 'Extent of illicit drug use and dependence, and their
contribution to the global burden of disease', The Lancet, vol. 379, no. 9810, pp. 55-70.
Degenhardt, L, Ferrari, AJ, Calabria, B, Hall, WD, Norman, RE, McGrath, J, Flaxman,
AD, Engell, RE, Freedman, GD, Whiteford, HA & Vos, T 2013, 'The Global
Epidemiology and Contribution of Cannabis Use and Dependence to the Global
Burden of Disease: Results from the GBD 2010 Study', PLoS ONE, vol. 8, no. 10, p.
e76635.
Di Chiara, G & Imperato, A 1988, 'Drugs abused by humans preferentially increase
synaptic dopamine concentrations in the mesolimbic system of freely moving rats',
Proceedings of the National Academy of Sciences of the United States of America, vol.
85, no. 14, pp. 5274-5278.
Diana, M, Melis, M, Muntoni, AL & Gessa, GL 1998, 'Mesolimbic dopaminergic
decline after cannabinoid withdrawal', Proceedings of the National Academy of
Sciences of the United States of America, vol. 95, no. 17, pp. 10269-10273.
Fadda, P, Scherma, M, Spano, MS, Salis, P, Melis, V, Fattore, L & Fratta, W 2006,
'Cannabinoid self-administration increases dopamine release in the nucleus
accumbens', NeuroReport, vol. 17, no. 15, Oct 23, pp. 1629-1632.
French, ED, Dillon, K & Wu, X 1997, 'Cannabinoids excite dopamine neurons in the
ventral tegmentum and substantia nigra', NeuroReport, vol. 8, no. 3, pp. 649-652.
Gardner, EL, Paredes, W, Smith, D, Donner, A, Milling, C, Cohen, D & Morrison, D
1988, 'Facilitation of brain stimulation reward by Δ9-tetrahydrocannabinol',
Psychopharmacology, vol. 96, no. 1, pp. 142-144.
Gardner, EL & Vorel, SR 1998, 'Cannabinoid transmission and reward-related events',
Neurobiology of Disease, vol. 5, no. 6, pp. 502-533.
Gray, KM, Hart, CL, Christie, DK & Upadhyaya, HP 2008, 'Tolerability and effects
of oral Δ9-tetrahydrocannabinol in older adolescents with marijuana use disorders',
Pharmacology, Biochemistry and Behavior, vol. 91, no. 1, pp. 67-70.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 24 of 29
Green, B, Kavanagh, D & Young, R 2003, 'Being stoned: A review of self-reported
cannabis effects', Drug and Alcohol Review, vol. 22, no. 4, pp. 453-460.
Griffiths, RR, Bradford, LD & Brady, JV 1979, 'Progressive ratio and fixed ratio
schedules of cocaine-maintained responding in baboons', Psychopharmacology, vol.
65, no. 2, pp. 125-136.
Haney, M, Comer, SD, Ward, AS, Foltin, RW & Fischman, MW 1997, 'Factors
influencing marijuana self-administration by humans', Behavioural Pharmacology,
vol. 8, no. 2-3, pp. 101-112.
Haney, M, Ward, AS, Comer, SD, Foltin, RW & Fischman, MW 1999, 'Abstinence
symptoms following oral THC administration to humans', Psychopharmacology, vol.
141, no. 4, pp. 385-394.
Hart, CL, Haney, M, Ward, AS, Fischman, MW & Foltin, RW 2002, 'Effects of oral
THC maintenance on smoked marijuana self-administration', Drug and Alcohol
Dependence, vol. 67, no. 3, pp. 301-309.
Hartman, RL, Brown, TL, Milavetz, G, Spurgin, A, Gorelick, DA, Gaffney, G &
Huestis, MA 2015, 'Controlled vaporized cannabis, with and without alcohol:
Subjective effects and oral fluid-blood cannabinoid relationships', Drug Testing and
Analysis, vol. 8, no. 7, pp. 690-701.
Hasin, DS, Saha, TD, Kerridge, BT, Goldstein, RB, Chou, SP, Zhang, H, Jung, J,
Pickering, RP, Ruan, WJ & Smith, SM 2015, 'Prevalence of marijuana use disorders
in the United States between 2001-2002 and 2012-2013', JAMA Psychiatry, vol. 72,
no. 12, pp. 1235-1242.
Hutcheson, DM, Tzavara, ET, Smadja, C, Valjent, E, Roques, BP, Hanoune, J &
Maldonado, R 1998, 'Behavioural and biochemical evidence for signs of abstinence in
mice chronically treated with Δ-9-tetrahydrocannabinol', British Journal of
Pharmacology, vol. 125, no. 7, pp. 1567-1577.
Jarbe, TUC, Henriksson, BG & Ohlin, GC 1977, 'Δ9-THC as a discriminative cue in
pigeons: effects of Δ8-THC, CBD, and CBN', Archives Internationales de
Pharmacodynamie et de Therapie, vol. 228, no. 1, pp. 68-72.
Jones, BE & Prada, JA 1977, 'Effects of methadone and morphine maintenance on
drug-seeking behavior in the dog', Psychopharmacology, vol. 54, no. 2, pp. 109-112.
Jones, RT, Benowitz, N & Bachman, J 1976, 'Clinical studies of cannabis tolerance
and dependence', Annals of the New York Academy of Sciences, vol. 282, pp. 221-239.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 25 of 29
Justinova, Z, Tanda, G, Redhi, GH & Goldberg, SR 2003, 'Self-administration of Δ9-
tetrahydrocannabinol (THC) by drug naive squirrel monkeys', Psychopharmacology,
vol. 169, no. 2, pp. 135-140.
Justinova, Z, Tanda, G, Munzar, P & Goldberg, SR 2004, 'The opioid antagonist
naltrexone reduces the reinforcing effects of Δ9-tetrahydrocannabinol (THC) in
squirrel monkeys', Psychopharmacology, vol. 173, no. 1, pp. 186-194.
Justinova, Z, Goldberg, SR, Heishman, SJ & Tanda, G 2005, 'Self-administration of
cannabinoids by experimental animals and human marijuana smokers', Pharmacology,
Biochemistry and Behavior, vol. 81, no. 2, pp. 285-299.
Katsidoni, V, Anagnostou, I & Panagis, G 2013, 'Cannabidiol inhibits the reward-
facilitating effect of morphine: Involvement of 5-HT1A receptors in the dorsal raphe
nucleus', Addiction Biology, vol. 18, no. 2, pp. 286-296.
Kaymakcalan, S 1972, 'Physiology and psychological dependence on THC in rhesus
monkeys', in WDM Paton & J Crown (eds), Cannabis and It's Derivatives, Oxford
University Press, London, pp. 142-146.
Kelleher, RT & Goldberg, SR 1977, 'Fixed-interval responding under second-order
schedules of food presentation or cocaine injection', Journal of the Experimental
Analysis of Behavior, vol. 28, no. 3, pp. 221-231.
Kelly, TH, Foltin, RW, Emurian, CS & Fischman, MW 1997, 'Are choice and self-
administration of marijuana related to Δ 9-THC content?', Experimental and Clinical
Psychopharmacology, vol. 5, no. 1, pp. 74-82.
Klein, C, Karanges, E, Spiro, A, Wong, A, Spencer, J, Huynh, T, Gunasekaran, N,
Karl, T, Long, LE, Huang, XF, Liu, K, Arnold, JC & McGregor, IS 2011,
'Cannabidiol potentiates Δ 9-tetrahydrocannabinol (THC) behavioural effects and
alters THC pharmacokinetics during acute and chronic treatment in adolescent rats',
Psychopharmacology, vol. 218, no. 2, pp. 443-457.
Kleinloog, D, Roozen, F, De Winter, W, Freijer, J & Van Gerven, J 2014, 'Profiling
the subjective effects of Δ9-tetrahydrocannabinol using visual analogue scales',
International Journal of Methods in Psychiatric Research, vol. 23, no. 2, pp. 245-256.
Le Foll, B, Wiggins, M & Goldberg, SR 2006, 'Nicotine pre-exposure does not
potentiate the locomotor or rewarding effects of Δ-9-tetrahydrocannabinol in rats',
Behavioural Pharmacology, vol. 17, no. 2, pp. 195-199.
Lee, D, Schroeder, JR, Karschner, EL, Goodwin, RS, Hirvonen, J, Gorelick, DA &
Huestis, MA 2014, 'Cannabis withdrawal in chronic, frequent cannabis smokers
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 26 of 29
during sustained abstinence within a closed residential environment', American
Journal on Addictions, vol. 23, no. 3, pp. 234-242.
Lepore, M, Vorel, SR, Lowinson, J & Gardner, EL 1995, 'Conditioned place
preference induced by Δ9-tetrahydrocannabinol: comparison with cocaine, morphine,
and food reward', Life Sciences, vol. 56, no. 23-24, pp. 2073-2080.
Lepore, M, Liu, X, Savage, V, Matalon, D & Gardner, EL 1996, 'Genetic differences
in Δ9-tetrahydrocannabevol-induced facilitation of brain stimulation reward as
measured by a rate-frequency curve-shift electrical brain stimulation paradigm in
three different rat strains', Life Sciences, vol. 58, no. 25, pp. PL365-PL372.
Lile, JA, Kelly, TH, Pinsky, DJ & Hays, LR 2009, 'Substitution profile of Δ(9)-
tetrahydrocannabinol, triazolam, hydromorphone and methylphenidate in humans
discriminating Δ(9)-tetrahydrocannabinol', Psychopharmacology, vol. 203, no. 2, pp.
241-250.
Lile, JA, Kelly, TH & Hays, LR 2010, 'Substitution profile of the cannabinoid agonist
nabilone in human subjects discriminating delta9-tetrahydrocannabinol', Clinical
Neuropharmacology, vol. 33, no. 5, pp. 235-242.
Madras, BK 2015 Update of cannabis and its medical use, WHO 37th ECDD, 2015
http://www.who.int/medicines/access/controlled-
substances/6_2_cannabis_update.pdf?ua=1
McKeon, A, Frye, MA & Delanty, N 2008, 'The alcohol withdrawal syndrome',
Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 8, pp. 854-862.
Mechoulam, R & Hanuš, L 2002, 'Cannabidiol: An overview of some chemical and
pharmacological aspects. Part I: Chemical aspects', Chemistry and Physics of Lipids,
vol. 121, no. 1-2, pp. 35-43.
Mello, NK 1991, 'Preclinical evaluation of the effects of buprenorphine, naltrexone
and desipramine on cocaine self-administration', NIDA research monograph, vol. 105,
pp. 189-195.
Mendelson, JH & Mello, NK 1984, 'Reinforcing properties of oral delta 9-
tetrahydrocannabinol, smoked marijuana, and nabilone: influence of previous
marijuana use', Psychopharmacology, vol. 83, no. 4, pp. 351-356.
Munzar, P, Yasar, S, Redhi, GH, Justinova, Z & Goldberg, SR 2001, 'High rates of
midazolam self-administration in squirrel monkeys', Behavioural Pharmacology, vol.
12, no. 4, pp. 257-265.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 27 of 29
Notcutt, W, Langford, R, Davies, P, Ratcliffe, S & Potts, R 2012, 'A placebo-
controlled, parallel-group, randomized withdrawal study of subjects with symptoms of
spasticity due to multiple sclerosis who are receiving long-term Nabiximols
(nabiximols)', Multiple Sclerosis Journal, vol. 18, no. 2, pp. 219-228.
Oleson, EB & Cheer, JF 2012, 'A brain on cannabinoids: the role of dopamine release
in reward seeking', Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 8.
Perez-Reyes, M, Di Guiseppi, S, Davis, KH, Schindler, VH & Cook, CE 1982,
'Comparison of effects of marihuana cigarettes to three different potencies', Clinical
Pharmacology and Therapeutics, vol. 31, no. 5, May, pp. 617-624.
Petwee, RG 2008, 'The diverse CB1 and CB2 receptor pharmacology of three plant
cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ
9-tetrahydrocannabivarin',
British Journal of Pharmacology, vol. 153, pp. 199-215.
Pierce, RC & Kumaresan, V 2006, 'The mesolimbic dopamine system: the final
common pathway for the reinforcing effect of drugs of abuse?', Neuroscience and
Biobehavioral Reviews, vol. 30, no. 2, pp. 215-238.
Robson, P 2011, 'Abuse potential and psychoactive effects of δ-9-
tetrahydrocannabinol and cannabidiol oromucosal spray (Nabiximols), a new
cannabinoid medicine', Expert Opinion on Drug Safety, vol. 10, no. 5, pp. 675-685.
Rossetti, ZL, Hmaidan, Y & Gessa, GL 1992, 'Marked inhibition of mesolimbic
dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine
abstinence in rats', European Journal of Pharmacology, vol. 221, no. 2-3, pp. 227-234.
Sannerud, CA, Prada, J, Goldberg, DM & Goldberg, SR 1994, 'The effects of
sertraline on nicotine self-administration and food-maintained responding in squirrel
monkeys', European Journal of Pharmacology, vol. 271, no. 2-3, pp. 461-469.
Sañudo-Peña, MC, Tsou, K, Delay, ER, Hohman, AG, Force, M & Walker, JM 1997,
'Endogenous cannabinoids as an aversive or counter-rewarding system in the rat',
Neuroscience Letters, vol. 223, no. 2, pp. 125-128.
Schoedel, KA, Chen, N, Hilliard, A, White, L, Stott, C, Russo, E, Wright, S, Guy, G,
Romach, MK & Sellers, EM 2011, 'A randomized, double-blind, placebo-controlled,
crossover study to evaluate the subjective abuse potential and cognitive effects of
nabiximols oromucosal spray in subjects with a history of recreational cannabis use',
Human Psychopharmacology, vol. 26, no. 3, pp. 224-236.
Schramm-Sapyta, NL, Cha, YM, Chaudry, S, Wilson, WA, Swartzwelder, HS &
Kuhn, CM 2007, 'Differential anxiogenic, aversive, and locomotor effects of THC in
adolescent and adult rats', Psychopharmacology, vol. 191, pp. 867-877.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 28 of 29
Sellers, EM, Schoedel, K, Bartlett, C, Romach, M, Russo, EB, Stott, CG, Wright, S,
White, L, Duncombe, P & Chen, CF 2013, 'A multiple-dose, randomized, double-
blind, placebo-controlled, parallel-group QT/QTc study to evaluate the
electrophysiologic effects of THC/CBD spray', Clinical Pharmacology in Drug
Development, vol. 2, no. 3, pp. 285-294.
Serpell, MG, Notcutt, W & Collin, C 2013, 'Nabiximols long-term use: An open-label
trial in patients with spasticity due to multiple sclerosis', Journal of Neurology, vol.
260, no. 1, pp. 285-295.
Spear, DJ, Muntaner, C, Goldberg, SR & Katz, JL 1991, 'Methohexital and cocaine
self-administration under fixed-ratio and second-order schedules', Pharmacology,
Biochemistry and Behavior, vol. 38, no. 2, pp. 411-416.
Swedberg, MDB & Giarola, A 2015, 'Drug Discrimination: Use in Preclinical
Assessment of Abuse Liability', Nonclinical Assessment of Abuse Potential for New
Pharmaceuticals, Elsevier Inc., pp. 101-127.
Takahashi, RN & Singer, G 1979, 'Self-administration of Δ9-tetrahydrocannabinol by
rats', Pharmacology, Biochemistry and Behavior, vol. 11, no. 6, pp. 737-740.
Tanda, G, Pontieri, FE & Di Chiara, G 1997, 'Cannabinoid and heroin activation of
mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism',
Science, vol. 276, no. 5321, Jun 27, pp. 2048-2050.
Tanda, G, Loddo, P & Di Chiara, G 1999, 'Dependence of mesolimbic dopamine
transmission on delta9-tetrahydrocannabinol', European Journal of Pharmacology,
vol. 376, no. 1-2, Jul 2, pp. 23-26.
Tanda, G, Munzar, P & Goldberg, SR 2000, 'Self-administration behavior is
maintained by the psychoactive ingredient of marijuana in squirrel monkeys', Nature
Neuroscience, vol. 3, no. 11, pp. 1073-1074.
UNODC 2016, World Drug Report 2016, United Nations Office on Drugs and Crime,
Vienna, Austria.
Vandrey, RG, Budney, AJ, Moore, BA & Hughes, JR 2005, 'A cross-study
comparison of cannabis and tobacco withdrawal', American Journal on Addictions,
vol. 14, no. 1, pp. 54-63.
Vandrey, RG, Budney, AJ, Hughes, JR & Liguori, A 2008, 'A within-subject
comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and
both substances', Drug and Alcohol Dependence, vol. 92, no. 1-3, pp. 48-54.
38th
ECDD (2016) Agenda item 5.1 Cannabis Update
Page 29 of 29
Vann, RE, Gamage, TF, Warner, JA, Marshall, EM, Taylor, NL, Martin, BR & Wiley,
JL 2008, 'Divergent effects of cannabidiol on the discriminative stimulus and place
conditioning effects of Δ9-tetrahydrocannabinol', Drug and Alcohol Dependence, vol.
94, no. 1-3, pp. 191-198.
Vann, RE, Warner, JA, Bushell, K, Huffman, JW, Martin, BR & Wiley, JL 2009,
'Discriminative stimulus properties of Δ9-tetrahydrocannabinol (THC) in C57Bl/6J
mice', European Journal of Pharmacology, vol. 615, no. 1-3, pp. 102-107.
Vlachou, S, Nomikos, GG, Stephens, DN & Panagis, G 2007, 'Lack of evidence for
appetitive effects of Δ9- tetrahydrocannabinol in the intracranial self-stimulation and
conditioned place preference procedures in rodents', Behavioural Pharmacology, vol.
18, no. 4, pp. 311-319.
Vlachou, S & Panagis, G 2014, 'Regulation of brain reward by the endocannabinoid
system: a critical review of behavioral studies in animals', Current Pharmaceutical
Design, vol. 20, no. 13, pp. 2072-2088.
Wade, DT, Makela, PM, House, H, Bateman, C & Robson, P 2006, 'Long-term use of
a cannabis-based medicine in the treatment of spasticity and other symptoms in
multiple sclerosis', Multiple Sclerosis, vol. 12, no. 5, pp. 639-645.
Wagner, FA & Anthony, JC 2002 'From first drug use to drug dependence:
developmental periods or risk for dependence upon marijuana, cocaine and alcohol',
Neuropsychopharmacology, vol. 26, pp. 479-488.
Wakeford, GP, Wetzell, BB, Pomfrey, RL, Clasen, M, Taylor, W & Riley, AL 2016,
'Delta-9-Tetrahydrocannabinol (THC) Self-Administration in Male and Female Long
Evans Rats', The FASEB Journal, vol. 30, no. 703.1.
Wiley, JL, Lowe, JA, Balster, RL & Martin, BR 1995, 'Antagonism of the
discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus
monkeys', Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 1,
pp. 1-6.
Zuardi, AW 2008, 'Cannabidiol: From an inactive cannabinoid to a drug with wide
spectrum of action', Revista Brasileira de Psiquiatria, vol. 30, no. 3, pp. 271-280.
Top Related